Estimating treatment effects for individual patients based on the results of randomised clinical trials

Objectives To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect

Complex interventions for preventing diabetic foot ulceration

BACKGROUND: Ulceration of the feet, which can lead to the amputation of feet and legs, is a major problem for people with diabetes mellitus, and can cause substantial economic burden. Single preventive strategies have not been shown to reduce the incidence of foot ulceration to a significant extent. Therefore, in clinical practice, preventive interventions directed at patients, healthcare providers and/or the structure of health care are often combined (complex interventions). OBJECTIVES: To assess the effectiveness of complex interventions in the prevention of foot ulcers in people with diabetes mellitus compared with single interventions, usual care or alternative complex interventions. A complex intervention is defined as an integrated care approach, combining two or more prevention strategies on at least two different levels of care: the patient, the healthcare provider and/or the structure of health care. SEARCH METHODS: For the second update we searched the Cochrane Wounds Group Specialised Register (searched 22 May 2015), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 4), The Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2015, Issue 4), The Health Technology Assessment Database (HTA) (The Cochrane Library 2015, Issue 4), The NHS Economic Evaluation Database (NHS EED) (The Cochrane Library 2015, Issue 4), Ovid MEDLINE (1946 to 22 May 2015), Ovid MEDLINE (In-Process & Other Non-Indexed Citations 21 May, 2015), Ovid EMBASE (1974 to 21 May, 2015) and EBSCO CINAHL (1982 to 22 May, 2015). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) which compared the effectiveness of combinations of preventive strategies, not solely patient education, for the prevention of foot ulcers in people with diabetes mellitus, with single interventions, usual care or alternative complex interventions. DATA COLLECTION AND ANALYSIS: Two review authors were assigned to independently select studies, to extract study data and to assess risk of bias of included studies, using predefined criteria. MAIN RESULTS: Only six RCTs met the criteria for inclusion. The study characteristics differed substantially in terms of healthcare settings, the nature of the interventions studied and outcome measures reported. In three studies that compared the effect of an education-centred complex intervention with usual care or written instructions, only little evidence of benefit was found. Three studies compared the effect of more intensive and comprehensive complex interventions with usual care. One study found a significant and cost-effective reduction, one of lower extremity amputations (RR 0.30, 95% CI 0.31 to 0.71). One other study found a significant reduction of both amputation and foot ulcers. The last study reported improvement of patients' self care behaviour. All six included RCTs were at high risk of bias, with hardly any of the predefined quality assessment criteria met. AUTHORS' CONCLUSIONS: There is no high-quality research evidence evaluating complex interventions for preventing diabetic foot ulceration and insufficient evidence of benefit

Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women

Background The value of aspirin in primary prevention of cancer and cardiovascular disease (CVD) remains unclear. The aim of this study was to identify women who bene fit from alternate-day aspirin with regard to all relevant outcomes, including cancer, CVD and major gastrointestinal bleeding. Methods Long term follow-up data of 27 939 healthy women with baseline plasma samples in the Women's Health Study, a randomised trial of 100 mg alternate-day aspirin versus placebo, were used to develop competing risks models for individualised prediction of absolute risk reduction of the combination of CVD, cancer and major gastrointestinal bleeding by aspirin. Results Although aspirin was associated with a modestly decreased 15-year risk of colorectal cancer, CVD, and in some women non-colorectal cancer, aspirin treatment resulted in a negative treatment effect in the majority of women if gastrointestinal bleeding was also taken into account. The excess risk of major gastrointestinal bleeding by aspirin increased with age, but the benefits for colorectal cancer and CVD risk were also greater at higher age. Decision curves indicated that selective treatment of women ?65 years may improve net benefit compared to treating all, none and prediction-based treatment. The observed 15-year number needed to treat to prevent one event among women ?65 years was 29 (95% CI 12 to 102). Conclusions Concurrent evaluation of the absolute effects on cancer, CVD and major gastrointestinal bleeding showed that alternate-day use of low-dose aspirin is ineffective or harmful in the majority of women in primary prevention. Selective treatment of women ?65 years with aspirin may improve net benefit. Trial registration number NCT00000479

Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women

Background The value of aspirin in primary prevention of cancer and cardiovascular disease (CVD) remains unclear. The aim of this study was to identify women who bene fit from alternate-day aspirin with regard to all relevant outcomes, including cancer, CVD and major gastrointestinal bleeding. Methods Long term follow-up data of 27 939 healthy women with baseline plasma samples in the Women's Health Study, a randomised trial of 100 mg alternate-day aspirin versus placebo, were used to develop competing risks models for individualised prediction of absolute risk reduction of the combination of CVD, cancer and major gastrointestinal bleeding by aspirin. Results Although aspirin was associated with a modestly decreased 15-year risk of colorectal cancer, CVD, and in some women non-colorectal cancer, aspirin treatment resulted in a negative treatment effect in the majority of women if gastrointestinal bleeding was also taken into account. The excess risk of major gastrointestinal bleeding by aspirin increased with age, but the benefits for colorectal cancer and CVD risk were also greater at higher age. Decision curves indicated that selective treatment of women ?65 years may improve net benefit compared to treating all, none and prediction-based treatment. The observed 15-year number needed to treat to prevent one event among women ?65 years was 29 (95% CI 12 to 102). Conclusions Concurrent evaluation of the absolute effects on cancer, CVD and major gastrointestinal bleeding showed that alternate-day use of low-dose aspirin is ineffective or harmful in the majority of women in primary prevention. Selective treatment of women ?65 years with aspirin may improve net benefit. Trial registration number NCT00000479

The current situation of the usage of websites to vitalize knowledge sharing in depopulated rural areas.:Focusing on a web-site "Sato-Net" deployed in Sasayama City, Hyogo Prefecture

textabstractObjectives: To enable risk stratification of patients with various types of arterial disease by the development and validation of models for prediction of recurrent vascular event risk based on vascular risk factors, imaging or both. Design: Prospective cohort study. Setting: University Medical Centre. Patients: 5788 patients referred with various clinical manifestations of arterial disease between January 1996 and February 2010. Main outcome measures: 788 recurrent vascular events (ie, myocardial infarction, stroke or vascular death) that were observed during 4.7 (IQR 2.3 to 7.7) years' follow-up. Results: Three Cox proportional hazards models for prediction of 10-year recurrent vascular event risk were developed based on age and sex in addition to clinical parameters (model A), carotid ultrasound findings (model B) or both (model C). Clinical parameters were medical history, current smoking, systolic blood pressure and laboratory biomarkers. In a separate part of the dataset, the concordance statistic of model A was 0.68 (95% CI 0.64 to 0.71), compared to 0.64 (0.61 to 0.68) for model B and 0.68 (0.65 to 0.72) for model C. Goodness-of-fit and calibration of model A were adequate, also in separate subgroups of patients having coronary, cerebrovascular, peripheral artery or aneurysmal disease. Model A predicted <20% risk in 5

Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease

Objective In statin-treated patients with stable coronary artery disease (CAD), residual risk of cardiovascular events is partly explained by plasma levels of low-density lipoprotein cholesterol (LDL-C). This study aimed to estimate individual benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in CAD patients already treated with high-dose statin. Methods Individual lifetime benefit was estimated in months gain free of stroke or myocardial infarction (MI) until age 80 years. Predictions were based on two competing risk models developed in data from 4853 patients with CAD originating from the atorvastatin 80 mg arm of the Treating to New Targets (TNT) trial. The relative effect of PCSK9 inhibition was added to the models and was assumed based on average estimates from large clinical trials. We accounted for individual LDL-C levels, assuming 50% LDL-C reduction by PCSK9 inhibition and 21% cardiovascular risk reduction per mmol/L (39 mg/dL) LDL-C lowering. Results Estimated individual gain was 1.8 mmol/L (>70 mg/dL). Estimated benefit was lowest (≤5 months) in older patients (≥70 years), in particular if LDL-C and other risk factors levels were low. Conclusion The individual estimated lifetime benefit from PCSK9 inhibition in patients with stable CAD on high-dose statin varied from <6 to ≥12 months free of stroke or MI. Highest benefit is expected in younger patients (age 40-60 years) with high risk factor burden and relatively high LDL-C levels

High-dose statin therapy in patients with stable coronary artery disease: treating the right patients based on individualized prediction of treatment effect

Clinicians need to identify coronary artery disease patients for whom the benefits of high-dose versus usual-dose statin therapy outweigh potential harm. We therefore aimed to develop and validate a model for prediction of the incremental treatment effect of high-dose statins for individual patients in terms of reduction of 5-year absolute risk for myocardial infarction, stroke, coronary death, or cardiac resuscitation. Based on data from the Treating to New Targets trial (TNT; n=10 001), a Cox proportional hazards model was developed comprising 13 easy-to-measure clinical predictors: age, sex, smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, history of myocardial infarction, coronary artery bypass grafting, congestive heart failure or abdominal aortic aneurysm, glomerular filtration rate, and treatment status (ie, atorvastatin 80 mg or 10 mg). External validation in the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial (IDEAL; n=8888) confirmed adequate goodness-of-fit and calibration, but moderate discrimination (C-statistic, 0.63; 95% confidence interval, 0.62-0.65). Still, among participants of both trials combined, the model identified a group of 11.7% whose predicted 5-year number needed to treat was ≤25 and a group of 41.9% whose predicted needed to treat was ≥50. A decision curve shows that making treatment decisions on the basis of predictions using our model may improve net benefit. Estimation of the incremental treatment effect of high-dose versus usual-dose statin therapy in individual coronary artery disease patients enables selection of high-risk patients that benefit most from more aggressive therapy. http://www.clinicaltrials.gov. Unique identifiers: NCT00327691 and NCT0015983

Systemic inflammation decreases pain threshold in humans in vivo

Contains fulltext : 126271.pdf (publisher's version ) (Open Access)BACKGROUND: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. METHODS AND RESULTS: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-alpha, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20+/-4 % and 13+/-3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7+/-3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. CONCLUSIONS AND SIGNIFICANCE: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception